title: Optimization of benzodiazepinones as selective inhibitors of the X-linked inhibitor of apoptosis protein (XIAP) second baculovirus IAP repeat (BIR2) domain.
abstract: The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.
authors.affiliation: Departments of Discovery Chemistry, ‡Discovery Technologies, §Non-clinical Safety, Early ADME, and ∥Discovery Oncology, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kester
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Donnell
authors.forename: Yan
authors.initials: Y
authors.lastname: Lou
authors.forename: Stacy W
authors.initials: SW
authors.lastname: Remiszewski
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Chen
authors.forename: Nam T
authors.initials: NT
authors.lastname: Le
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lo
authors.forename: John A
authors.initials: JA
authors.lastname: Moliterni
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Han
authors.forename: J Heather
authors.initials: JH
authors.lastname: Hogg
authors.forename: Weiling
authors.initials: W
authors.lastname: Liang
authors.forename: Christophe
authors.initials: C
authors.lastname: Michoud
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Rupert
authors.forename: Steven
authors.initials: S
authors.lastname: Mischke
authors.forename: Kang
authors.initials: K
authors.lastname: Le
authors.forename: Martin
authors.initials: M
authors.lastname: Weisel
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lukacs
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Fretland
authors.forename: Kyoungja
authors.initials: K
authors.lastname: Hong
authors.forename: Ann
authors.initials: A
authors.lastname: Polonskaia
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.forename: Shirley
authors.initials: S
authors.lastname: Li
authors.forename: Dave S
authors.initials: DS
authors.lastname: Solis
authors.forename: Doug
authors.initials: D
authors.lastname: Aguilar
authors.forename: Christine
authors.initials: C
authors.lastname: Tardell
authors.forename: Mark
authors.initials: M
authors.lastname: Dvorozniak
authors.forename: Shahid
authors.initials: S
authors.lastname: Tannu
authors.forename: Edmund C
authors.initials: EC
authors.lastname: Lee
authors.forename: Andy D
authors.initials: AD
authors.lastname: Schutt
authors.forename: Barry
authors.initials: B
authors.lastname: Goggin
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001570:Benzodiazepinones; D006571:Heterocyclic Compounds; D051034:Inhibitor of Apoptosis Proteins; C586833:N-(5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2-(methylamino)propanamide; D051636:X-Linked Inhibitor of Apoptosis Protein; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; D053148:Caspase 3; D053179:Caspase 7; D000409:Alanine